Hypoxia is a potent stimulus for the growth of gas exchange organs across the animal kingdom. Our goal is to understand the mechanisms of compensatory lung growth induced by alveolar hypoxia at high altitude (HA) and the interaction with developmental lung growth. Our data show that postnatal alveolar growth is accelerated in young guinea pigs raised at HA (3,800m) leading to enhancement of lung and membrane diffusing capacities (DLco and Dmco) compared to matched controls raised at low altitude (1,200m). Acinar remodeling also develops with progressive alterations in acinar architecture and reductions in the mean harmonic thickness of the blood-gas barrier, an index of diffusive resistance to O2 uptake. Enhancement persists during up to 12 mo of HA exposure but may regress if the HA stimulus is withdrawn before the animals reach full maturity. These data raise important questions regarding the reversibility of the adaptive response and whether the response could be amplified. Our Specific Aims are to a) compare HA-induced adaptation in adult animals to that in immature animals; b) define the reversibility of HA-induced adaptation following return to LA in relationship to somatic maturity; c) explore whether exercise training enhances HA- induced lung growth and function; and d) determine the structural basis of alveolar remodeling in relationship to somatic maturity at HA. Separate cohort of immature (weanling) and mature (6 mo old)guinea pigs will be reside at HA or LA for different periods. Serial physiological measurements will include ventilation, gas exchange, lung volume, DLco, Dmco, pulmonary capillary blood volume (Vc)and cardiac output by anon- invasive rebreathing technique in the conscious spontaneously breathing animal at rest and during exercise. Some groups will return to LA before or after reaching somatic maturity for de-acclimatization in order to determine the permanence of HA-induced adaptation. Other groups will be either exercise trained or untrained during exposure in order to determine the training effect on adaptation. Terminally pressure- volume relationship of the lung and thorax will be measured. One lung will be sampled for molecular assays to assess the expression of paracrine erythropoietin (EPO)signaling pathway via the hypoxia-inducible transcriptional factors (HIF's) and their downstream effects. The other lung will be fixed for morphometric assessment of structural growth and remodeling. These studies will characterize the interactions between developmental and hypoxia-related growth signals, the processes by which structural adaptation leads to functional compensation, and explore one strategy for amplifying the endogenous adaptive response.